Depression is a chronic disease that affects people of all ages. Of various antidepressants currently used, the most successful one is a selective serotonin reuptake inhibitor (hereinafter, also abbreviated to SSRI). SSRIs have a higher serotonin reuptake inhibitory effect than dopamine and noradrenalin reuptake inhibitory effects. The first drug put on the market as an SSRI was zimelidine. Examples of other SSRIs subsequently launched or under development include fluoxetine, fluvoxamine, citalopram, sertraline, and paroxetine.
Although such SSRIs are widely used as therapeutic drugs for depression, it has been pointed out that they still have some problems. Typical examples thereof include the following problems: even SSRIs have an insufficient therapeutic effect on refractory depression patients, which occupy approximately ⅓ of all depression patients; and they require a period as long as 3 to 8 weeks for the onset of a sufficient antidepressant effect. Thus, the onset of the antidepressant effects of SSRIs is slow, whereas their side effects may immediately occur. Specifically, SSRIs present the problem of a vulnerable period during which patients undergo only the side effects of the drugs without obtaining their therapeutic effects. Therefore, treating physicians often bear a heavy burden of persuading patients to continuously take the same drugs even during the period. Furthermore, due to the slow onset of the antidepressant effect, patients at risk of attempting suicide restore their initiative before experiencing sufficient improvements in the symptoms of depression. Therefore, for example, they are threatened by suicide or needed to be repeatedly hospitalized. It has thus been demanded to develop an antidepressant with rapid onset of the antidepressant effect.
The reason why SSRIs require a period as long as a few weeks for the onset of an antidepressant effect may be as follows:
SSRIs inhibit acute serotonin reuptake of serotonin turnover. This inhibitory effect occurs in the nerve endings of serotonergic neurons and thereby enhances serotonin-mediated neurotransmission, resulting in the antidepressant effect. However, this inhibitory effect also occurs in cell bodies or dendrites of serotonergic neurons present in raphe nuclei and therefore enhances, in the raphe nuclei, serotonin 1A autoreceptor-mediated suppression (negative feedback reaction) of the spontaneous firing of the serotonergic neurons. As a result, neurotransmission in the serotonergic neurons is less enhanced than expected, as a whole, in the initial stage after SSRI administration. On the other hand, continuous SSRI administration for a few weeks desensitizes the serotonin 1A autoreceptor on cell bodies or dendrites of serotonergic neurons in raphe nuclei and thereby eliminates the negative feedback reaction. As a result, the enhanced activities of the serotonergic neurons in cooperation with serotonin uptake inhibition in the nerve endings successfully enhance serotonin neurotransmission, resulting in a sufficient antidepressant effect.
Thus, reduction in the period required for the onset of SSRI effects or potentiation of the antidepressant effect can be achieved by the combined use with a serotonin 1A receptor antagonist, which blocks the serotonin 1A autoreceptor and thereby eliminates the negative feedback reaction of serotonin, or by the combined use with a serotonin 1A receptor agonist, which actively stimulates the serotonin 1A autoreceptor to reduce a period required for desensitization. In actuality, it has been reported that the combined use of SSRI with pindolol having high affinity for serotonin 1A receptors potentiates the effect of the serotonin reuptake inhibitor on depression patients and reduces a period required for the onset of the effect (Arch, Gen. Psychiatry, (1994), 51, 248-251).
When patients take drugs, it is preferred that the drugs be fewer in number or type. Thus, based on the above findings, a compound having a serotonin reuptake inhibitory effect in combination with affinity for serotonin 1A receptors can probably be used as a novel antidepressant by itself without being combined with other drugs, and this novel antidepressant has a strong antidepressant effect and requires a reduced period for the onset of the effect. It has thus been desired to develop such a compound as a drug.
A previously reported compound having a serotonin reuptake inhibitory effect in combination with affinity for serotonin 1A receptors is a benzylpiperidine derivative having a substituted benzyl group at 4-position and a substituted phenylethyl group at 1-position (see e.g., PATENT DOCUMENT 1). Specifically, the document discloses serotonin reuptake inhibitors comprising, as an active ingredient, a cyclic amine or the like represented by the formula (A):
wherein each of plural R0 present independently represents a hydrogen atom, a halogen atom, an alkyl group, a substituted alkoxy group, or the like; R3 represents a hydrogen atom or the like; n represents an integer of 2 or the like; m represents an integer of 2 or the like; R5 and R6 each independently represent a hydrogen atom or the like; and Z represents a substituted aryl group or the like.The document further discloses that these serotonin reuptake inhibitors have serotonin 1A antagonistic activity.
On the other hand, a compound having a substituted benzyl group at 4-position of piperidine has been reported in plural documents. Examples thereof include a document that discloses cyclic amine derivatives acting as therapeutic drugs for cerebral vascular disorders (see PATENT DOCUMENT 2) and a document that discloses 4-substituted piperidines acting as NMDA receptor antagonists (see PATENT DOCUMENT 3).
Furthermore, a compound having a substituted phenylethyl group at 1-position of piperidine has also been reported in several documents. Indole derivatives having a piperidine ring having a cyclic ketone structure as a substituent on a phenylethyl group have been reported as 5-HT1A antagonists (see e.g., PATENT DOCUMENT 4). These indole derivatives have structural difference from the benzylpiperidine compounds having a substituted benzyl group at 4-position of piperidine. Moreover, it has not been reported that these indole derivatives also have a serotonin reuptake inhibitory effect.
None of these patent documents specifically disclose or suggest a benzylpiperidine compound that has a substituted benzyl group at 4-position of piperidine and further has, at 1-position of piperidine, a phenylethyl (phenethyl) group of which the benzene ring moiety is fused with a saturated ring comprising an oxo group.
Moreover, many antidepressants such as tricyclic antidepressants (TCAs) and SSRIs are known to have a strong inhibitory effect on the enzyme CYP2D6, one of the molecular species of human cytochrome P450, which participates in drug metabolism. On the other hand, it is also known that many therapeutic agents for psychiatric disorders that may be used in combination with TCA or SSRI in the treatment of depression or anxiety symptoms are metabolized by CYP2D6. Thus, in the combined use of these drugs, the CYP2D6 inhibitory effect of one of the drugs inhibits the metabolism of the other drug. The concentration of the latter drug in blood is increased accordingly, resulting in the possible severe side effects. Thus, an antidepressant having a weaker CYP2D6 inhibitory effect has a smaller drug interaction with a therapeutic agent for psychiatric disorders metabolized by CYP2D6 in the combined use. Therefore, such an antidepressant can be expected to serve as a highly safe drug. It has thus been demanded to develop the drug.
Furthermore, CYP2D6 is known to vary largely in enzyme activity among individuals due to genetic polymorphisms. Drugs metabolized at high rates by CYP2D6 vary largely in in-vivo drug concentration among individuals. Their drug concentrations in blood are highly possibly increased more largely in a poor metabolizer (PM) than in an extensive metabolizer (EM). Moreover, such drugs possibly exhibit a stronger drug interaction with a drug that inhibits CYP2D6 or is metabolized by CYP2D6. Thus, a lower rate of CYP2D6 contribution to drug metabolism offers a smaller pharmacokinetic influence by the genetic polymorphisms of CYP2D6. Therefore, such a drug can be expected to be highly safe. It has also been demanded to develop the drug.    PATENT DOCUMENT 1: U.S. Pat. No. 6,787,560    PATENT DOCUMENT 2: WO88/02365    PATENT DOCUMENT 3: WO97/23216    PATENT DOCUMENT 4: WO2005/108389